Brain Hexokinase I Expression and Function during Development. † 1391

Glucose, an essential substrate for brain growth, cellular maturation, and oxidative metabolism is transported across the blood-brain barrier, into neurons and glial cells. Intracellularly glucose is phosphorylated into glucose-6-phosphate by the hexokinase I (hxl) enzyme. In the adult brain, glucose phosphorylation comprises the rate-limiting step in the process of glucose uptake. To determine the ontogeny of this critical rate limiting step, we examined the brain hxl expression (Northern blots), concentration (Western blots), enzymatic activity (NADP→NADPH conversion by spectrophotometric assay) and function (³H-2-deoxy-glucose uptake) in Balb-C mice at 1d(n=6), 14d (n=6), and 35d (n=6) postnatal ages. Hxl mRNA and protein concentrations declined 20-50% (p < 0.05) while activity increased 2-fold between the 1d and 14d or 35d brains. In contrast, a six-fold increase in³ H-2-deoxy-glucose uptake (p < 0.05) which quantitates glucose transport and phosphorylation was noted between the 1d and 14d old mice. Our previous investigation demonstrated a 3-fold increase in brain glucose transporter expression and levels (particularly neuronal Glut 3) between the 1d and 14d mouse brains (Ped Res 39:91A, 1996). We conclude that 1] brain Hxl enzyme activity and function peak by a post-translational mechanism at the 14d postnatal age, 2] the age-related increase in brain Hxl enzyme activity along with the previous observation of a parallel increase in brain glucose transporter concentrations substantiate the age-related increase in brain 2-deoxyglucose uptake with a peak at 14d postnatal age. We speculate that this age-dependent increase in the mechanisms mediating brain glucose uptake 1] may be initiated by the physiological surge in thyroid hormone levels and activity that occurs at 14d of age, and 2] is critical for fueling the process of rapid brain growth and cellular development that occurs at 14d postnatal age in preparation for acquiring the specialized function of neurotransmission.

[Supported by NIH-HD 33997 & HL-52839].